1. Field of the Invention
This invention relates to uniaxial compression of an article, and more particularly, to uniaxial compression of a three-dimensionally printed object such as an oral dosage form.
2. Description of the Related Art
One of the most common methods of manufacturing an oral dosage form is by compressing powder into a desired shape using a die and press. This method is inexpensive and suitable for many pharmaceuticals. The powder that is pressed typically includes one or more Active Pharmaceutical Ingredients (API), pharmaceutical excipients (edible inert substances), and substances that help hold the tablet together after completion of pressing. The dosage forms produced by this method have typically been of homogeneous composition or, if they have had any inhomogeneity it has consisted of having a coating on the powder particles before they are pressed, or a coating around the entire tablet after it has been pressed. There has been no detailed or deterministic design of the interior of such a tablet and such design would not be possible with the prior art pressed tablet-manufacturing process.
A newer technique sometimes applied to the manufacture of pharmaceutical dosage forms, which allows the creation of detailed predetermined variation of composition within a dosage form, is three-dimensional printing (3DP). The basic technique is described in U.S. Pat. No. 5,204,055. In three-dimensional printing, which is illustrated in the three-dimensional printing apparatus 100 shown in FIG. 1, a layer of powder is created and then drops of a liquid called a binder liquid are dispensed onto the powder by a technique resembling ink-jet printing. At the places wetted by binder liquid, powder particles are joined to each other and to other solid regions. Then, another layer of powder is deposited and the process is repeated for successive layers until the desired three-dimensional object is created. Unbound powder supports printed regions until the article is sufficiently dry and then the unbound powder is removed. In making a dosage form by three-dimensional printing, an Active Pharmaceutical Ingredient is included in the printed article, most commonly by being contained in a binder liquid which is dispensed onto the pharmaceutical excipient powder. Three-dimensional printing allows for controlled placement of substances within the dosage form, and this has been used to achieve time-dependent release of one or more API, release of API only in an environment of a specified pH, etc. Three-dimensionally printed dosage forms requiring complex release profiles and/or multiple API, as has been described in commonly assigned U.S. Pat. No. 6,280,771.
However, several drawbacks have become apparent with oral dosage forms made by 3DP. One limitation has been that the surface of a 3DP printed part has typically been unacceptably rough as compared to traditionally manufactured pressed tablets. The dimensional scale of the surface texture corresponds to the thickness of the powder layers used in its fabrication. A typical minimum powder layer thickness, for the case of dry powder spread by rollers, is 0.004 to 0.008 inch (100 to 200 microns). This has conflicted with the expectations of consumers accustomed to smooth-surfaced oral dosage forms made by tablet pressing. Oral dosage forms with rough surfaces have been more difficult to swallow than smooth ones, and also rough surfaces have been friable, i.e., have presented possibilities for particles to break off during handling.
Another limitation was that when the API was deposited into the dosage form by being contained in the binder liquid, there have been limitations in terms of how much API could be delivered into the dosage form. Usually the API is delivered by being contained in the binder liquid, and the powder is a pharmaceutical excipient containing no API.
In 3DP the powder has typically been spread to an overall packing density of approximately 50% solid and 50% void. This packing density yields a dosage form that can only include at most 50% by volume of API. API may be delivered into the interstices of the dosage form by solution printing, i.e., with the API being dissolved in the binder liquid that is dispensed onto the powder. If the binder liquid exactly fills the void space and if for sake of example the API is soluble in the binder liquid to the extent of 20% on a volume basis, which is a fairly high solubility among substances of practical interest, then by filling the empty space completely with binder liquid and allowing the volatile part of the binder liquid to evaporate, 20% of the empty space could be filled with the API which had been dissolved in the binder liquid.
The result is that the volume distribution after this first printing becomes 50% excipient, 10% API and 40% void. It is possible to re-print the same region. If it is optimistically assumed that all of the remaining void is accessible to deposited liquid, the result would be to fill 20% of the remaining 40% empty volume, with the result that after evaporation the allocation of volume of the dosage form becomes excipient 50%, API 18%, and void 32%. If still another re-printing were performed, another 20% of that remaining empty volume could be filled, bringing the volume distribution to 50% excipient, 24.4% API content, and 25.6% void. Such a calculation is further illustrated in FIG. 3, which shows more generally that in order to achieve a certain dosage, corresponding pairs of API concentration and saturation parameter are needed.
In 3DP, the saturation parameter describes how much of the void volume is filled with liquid during a printing pass and is typically approximately equal to or less than 100%. Because of the need to deposit significant amounts of API, FIG. 2 extends the definition of saturation to define apparent saturation as extending to values greater than 100%, by using that parameter to refer to multi-pass printing on a given powder layer.
FIG. 3 is based on an assumed dosage form having dimensions of 5 mm diameter by 5 mm high. If one wants to deposit 100 mg of API into a 3DP printed article of these dimensions using an API solution with 20-wt % API concentration, then according to FIG. 2 it is necessary to print to an apparent saturation of 250%. This means that each area or layer would need to be printed, in effect, approximately 2.5 times using a saturation of 100% or in practice 3 times with a saturation of 83%, with intervening evaporation of the volatile part of the binder liquid. FIG. 3 presents the same calculated results as FIG. 2 but with the results presented in a normalized fashion, as mass of API deposited per unit volume of the API-containing region.
One method to eliminate void space in a 3DP printed API-containing article has been with cold isostatic pressing. (Formulation of Oral Dosage Forms by Three-Dimensional Printing, M.S. thesis at Massachusetts Institute of Technology, by Robert Palazzolo, February, 1998) This involved using hydrostatic pressure to press from all directions simultaneously on an article that had been enclosed in a temporary elastomeric bag or mold. It was understood that three-dimensional compression of the three-dimension ODF was required in order to maintain the three-dimensional internal structure and to preserve the release profile of the three-dimensional dosage form. Although cold isostatic pressure reduced some of the void space it did not satisfactorily address these other concerns. Additionally, cold isostatic pressing involved a number of inconvenient process steps, including creation of the temporary elastomeric mold or bag surrounding the printed article, immersion of the mold or bag in a confined liquid to apply the pressure, and removal of the mold or bag. Accordingly, cold isostatic pressing has not been well suited to mass production. Also, while it has improved the surface finish compared to the surface finish of the part after completion of 3DP, resulting in a surface finish as shown in FIG. 4, it has not eliminated surface roughness to an acceptable level.
Accordingly, there is still need for a technique that substantially eliminates void space or reduces void space to the extent desired; allows larger API loading; fits in well with mass production; maintains internal architecture and designed release profiles; and provides a commercially acceptable surface finish for three-dimensionally printed oral dosage forms.